STRUCTURE OF THE PROMETASTATIC ENZYME AUTOTAXIN

促转移酶自分泌因子的结构

• 批准号: 8169317
• 负责人: DEMETRIOS BRADDOCK
• 金额: $ 0.7万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169317
• 关键词: Brain; Cell Proliferation; Cell Surface Receptors; Chemicals; Choline; Computer Retrieval of Information on Scientific Projects Database; Development; Enzymes; Event; Foundations; Funding; GTP-Binding Proteins; Generations; Grant; Human; Hydrolysis; Institution; Lead; Lysophospholipids; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Neoplasm Metastasis; Organism; Ovarian Carcinoma; Peritoneal Fluid; Phospholipids; Play; Production; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Structure; Tumor Cell Invasion; United States National Institutes of Health; Vascular remodeling; Wound Healing; base; cell transformation; extracellular; inhibitor/antagonist; lysophosphatidic acid; malignant breast neoplasm; migration; neovascularization; overexpression; physical property; small molecule; therapeutic development; three dimensional structure; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NPP-2, also known as Autotaxin (ATX) hydrolyzes lysophosphatidyl choline into choline and lysophosphatidic acid (LPA), an extracellular signaling phospholipid that activates G-protein-coupled cell surface receptors, triggers cell proliferation, migration, and survival, and ultimately mediates events central to organism fate such as wound healing, brain development and vascular remodeling. Generation of extracellular LPA by ATX promotes tumor invasion, metastasis, and neovascularization of ras-transformed cells. The potent mitogenic activity in human ovarian cancer ascitic fluid is mediated by LPA4. In addition, ATX is markedly overexpressed in ovarian carcinoma, and the invasiveness of human breast cancer correlates directly with ATX expression. Despite the important roles LPA and ATX play in cell signaling, development and oncogenesis, understanding the basis and regulation of extracellular LPA synthesis has been limited by a lack of information regarding the chemical and physical properties of ATX, the only identified enzyme responsible for generating extracellular LPA. To understand how ATX-mediated LPA production contributes to cancer development and progression, and to identify and develop small molecule inhibitors of LPA, we determined the three dimensional structure of the human enzyme and identified lead small molecule inhibitors. These studies provide the foundation for the rational development of therapeutic compounds directed against an important pro-metastatic enzyme overexpressed in a variety of highly malignant tumors.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 NPP-2，也称为自身Xt蛋白（ATX）水解溶液磷脂酰胆碱成胆碱和溶血磷脂酸（LPA），这是一种细胞外信号磷脂，激活G蛋白偶联细胞表面受体，触发细胞的细胞增殖，迁移，以及生存，以及生存元素，以及有机体命运的核心事件，例如伤口愈合，脑发育和血管重塑。 通过ATX生成细胞外LPA可促进Ras转化细胞的肿瘤侵袭，转移和新生血管化。人卵巢癌液体中的有效有丝分裂活性是由LPA4介导的。 此外，ATX在卵巢癌中明显过表达，人类乳腺癌的侵入性直接与ATX表达相关。 尽管LPA和ATX在细胞信号传导，发育和肿瘤发生中起着重要作用，但了解细胞外LPA合成的基础和调节受到了缺乏有关ATX的化学和物理性能的信息，这是ATX的化学和物理性质的唯一识别酶，这是唯一负责产生细胞外的酶。 LPA。 为了了解ATX介导的LPA产生如何有助于癌症的发展和进展，并确定和发展LPA的小分子抑制剂，我们确定了人酶的三维结构，并鉴定出铅小分子抑制剂。这些研究为针对各种高度恶性肿瘤中过表达的重要促异常酶的治疗化合物的合理发展奠定了基础。